Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:Despite emerging studies on neighborhood-level risk factors for chronic kidney disease (CKD), our understanding of the causal links between neighborhood characteristics and CKD is limited. In particular, there is a gap in identifying modifiable neighborhood factors, such as the built environment, in preventing CKD, that could be targets for feasible place-based interventions. RECENT FINDINGS/RESULTS:Most published studies on neighborhood factors and CKD have focused on a single social attribute, such as neighborhood disadvantage, while research on the role of the built environment is more nascent. Early studies on this topic have yielded inconsistent results, particularly regarding whether food deserts are an environmental risk factor for CKD onset. International studies have shown that walkable neighborhoods - characterized by features such as urban design, park access, and green spaces - can be protective against both the onset and progression of CKD. However, these findings are inconclusive and understudied in the context of United States, where neighborhood environments differ from those in other countries. SUMMARY/CONCLUSIONS:Future research on modifiable neighborhood factors and CKD using advanced study designs and population-representative datasets can yield stronger evidence on potential causal associations and suggest feasible place-based interventions as strategies for preventing CKD. As an example, we demonstrated the potential of electronic health record-based studies to advance research in this area.

In 2017, Kidney Disease: Improving Global Outcomes (KDIGO) published a Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Since then, new lines of evidence have been published related to evaluating disordered mineral metabolism and bone quality and turnover, identifying and inhibiting vascular calcification, targeting vitamin D levels, and regulating parathyroid hormone. For an in-depth consideration of the new insights, in October 2023, KDIGO held a Controversies Conference on CKD-MBD: Progress and Knowledge Gaps Toward Personalizing Care. Participants concluded that the recommendations in the 2017 CKD-MBD guideline remained largely consistent with the available evidence. However, the framework of the 2017 Guideline, with 3 major sections-biochemical abnormalities in mineral metabolism; bone disease; and vascular calcification-may no longer best reflect currently available evidence related to diagnosis and treatment. Instead, future guideline efforts could consider mineral homeostasis and deranged endocrine systems in adults within a context of 2 clinical syndromes: CKD-associated osteoporosis, encompassing increased fracture risk in patients with CKD; and CKD-associated cardiovascular disease, including vascular calcification and structural abnormalities, such as valvular calcification and left ventricular hypertrophy. Participants emphasized that the complexity of bone and cardiovascular manifestations of CKD-MBD necessitates personalized approaches to management.

BACKGROUND:Cardiovascular risk models have been developed primarily for incident events. Well-performing models are lacking to predict secondary cardiovascular events among people with a history of coronary heart disease, stroke, or heart failure who also have chronic kidney disease (CKD). We sought to develop a proteomics-based risk score for cardiovascular events in individuals with CKD and a history of cardiovascular disease. METHODS:We measured 4638 plasma proteins among 1067 participants from the Chronic Renal Insufficiency Cohort (CRIC) and 536 individuals from the Atherosclerosis Risk in Communities Cohort (ARIC). All had non-dialysis-dependent CKD and coronary heart disease, heart failure, or stroke at study baseline. A proteomic risk model for secondary cardiovascular events was derived by elastic net regression in CRIC, validated in ARIC, and compared to clinical models. Biologic mechanisms of secondary events were characterized through proteomic pathway analysis. RESULTS:A 16-protein risk model was superior to the Framingham risk score for secondary events, including a modified score that included estimated glomerular filtration rate (eGFR). In CRIC, the annualized area under the receiver operating characteristic (AUC) within 1 to 5 years ranged between 0.77 and 0.80 for the protein model and 0.57 and 0.72 for the clinical models. These findings were replicated in the ARIC validation cohort. Biologic pathway analysis identified pathways and proteins for cardiac remodeling and fibrosis, vascular disease, and thrombosis. CONCLUSIONS:The proteomic risk model for secondary cardiovascular events outperformed clinical models based on traditional risk factors and eGFR.

AIMS/HYPOTHESIS/OBJECTIVE:39-47 mmol/mol [5.7-6.4%] or fasting glucose 5.6-6.9 mmol/l) is associated with elevated risks of microvascular and macrovascular complications. It is unknown to what extent these risks in prediabetes remain after accounting for progression to diabetes. METHODS:In 10,310 participants from the Atherosclerosis Risk in Communities (ARIC) Study (aged 46-70 years, ~55% women, ~20% Black adults) without diabetes at baseline (1990-1992), we used Cox regression to characterise age- and sex-adjusted associations of prediabetes with ~30 year incidence of complications (composite and separately), including atherosclerotic CVD (ASCVD), heart failure, chronic kidney disease (CKD) and all-cause mortality before and after accounting for intervening incidence of diabetes, modelled as a time-varying variable. We calculated the excess risk of complications in prediabetes remaining after accounting for progression to diabetes. RESULTS:Of the 60% of adults with prediabetes at baseline, ~30% progressed to diabetes (median time to diabetes, 7 years). Over the maximum follow-up of ~30 years, there were 7069 events (1937 ASCVD, 2109 heart failure, 3288 CKD and 4785 deaths). Prediabetes was modestly associated with risk of any complication (HR 1.21 [95% CI 1.15, 1.27]) vs normoglycaemia. This association remained significant after accounting for progression to diabetes (HR 1.18 [95% CI 1.12, 1.24]) with 85% (95% CI 75, 94%) of the excess risk of any complication in prediabetes remaining. Results were similar for the individual complications. CONCLUSIONS/INTERPRETATION/CONCLUSIONS:Progression to diabetes explained less than one-quarter of the risks of clinical outcomes associated with prediabetes. Prediabetes contributes to the risk of clinical outcomes even without progression to diabetes.

KEY POINTS:In diabetes and CKD, creatinine- and cystatin C–based eGFR has a strong inverse correlation with plasma TNF receptor 1, TNF receptor 2, and soluble urokinase-type plasminogen activator receptor. Higher plasma soluble TNF receptors 1 and 2 and soluble urokinase-type plasminogen activator receptor were each individually associated with mortality, independent of baseline kidney measures. BACKGROUND:Several plasma biomarkers of kidney health have been associated with CKD progression in persons with diabetes, but their associations with mortality risk have been largely unexplored. METHODS:from the REGARDS cohort study, Cox proportional hazards regression was used to determine hazard ratios of mortality by plasma concentrations of soluble TNF receptors 1 and 2 (TNFR1 and TNFR2), soluble urokinase-type plasminogen activator receptor (suPAR), kidney injury molecule 1 (KIM-1), chitinase 3–like 1 (YKL-40), and monocyte chemotactic protein 1 (MCP-1). Covariates included sociodemographic and clinical factors, urine albumin-to-creatinine ratio (UACR), and creatinine- and cystatin C–based eGFR (eGFRcr-cys). RESULTS:=−0.10 to −0.40). With a median follow-up of 7 years, 332 participants died. In models adjusted for sociodemographic and clinical factors, each SD higher baseline concentration of plasma TNFR1 (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.20 to 1.38), TNFR2 (HR, 1.61; 95% CI, 1.42 to 1.82), suPAR (HR, 1.33; 95% CI, 1.22 to 1.44), KIM-1 (HR, 1.20; 95% CI, 1.08 to 1.33), and YKL-40 (HR, 1.23; 95% CI, 1.11 to 1.38) was associated with higher risk of all-cause mortality, whereas MCP-1 was not. Upon further adjustment for baseline eGFRcr-cys and UACR, only the associations for TNFR1 (HR, 1.16; 95% CI, 1.04 to 1.29), TNFR2 (HR, 1.34; 95% CI, 1.12 to 1.60), and suPAR (HR, 1.23; 95% CI, 1.11 to 1.36) persisted. CONCLUSIONS:Among adults with diabetes and CKD, higher plasma TNFR1, TNFR2, and suPAR were associated with all-cause mortality, independent of baseline kidney function.

RATIONALE & OBJECTIVE/UNASSIGNED:Diabetic kidney disease (DKD) is one of the leading causes of end-stage kidney disease globally. We aim to identify proteomic and metabolomic correlates of histologically confirmed DKD that may improve our understanding of its pathophysiology. STUDY DESIGN/UNASSIGNED:A cross-sectional study. SETTING & PARTICIPANTS/UNASSIGNED:A total of 434 Boston Kidney Biopsy Cohort participants. PREDICTORS/UNASSIGNED:Histopathological diagnosis of DKD on biopsy. OUTCOMES/UNASSIGNED:Proteins and metabolites associated with DKD. ANALYTICAL APPROACH/UNASSIGNED:We performed linear regression to identify circulating proteins and metabolites associated with a histopathological diagnosis of DKD (n = 81) compared with normal or thin basement membrane (n = 27), and other kidney diseases without diabetes (n = 279). Pathway enrichment analysis was used to explore biological pathways enriched in DKD. Identified proteins were assessed for their discriminative ability in cases of DKD versus a distinct set of 48 patients with diabetes but other kidney diseases. RESULTS/UNASSIGNED: = 0.008). LIMITATIONS/UNASSIGNED:A cross-sectional approach and lack of an external validation cohort. CONCLUSIONS/UNASSIGNED:Distinct proteins and biological pathways are correlated with a histopathological diagnosis of DKD.

RATIONALE & OBJECTIVE/UNASSIGNED:Individuals with chronic kidney disease (CKD) are at increased risk of morbidity and mortality, particularly as they progress to kidney failure. Identifying circulating proteins that underlie kidney failure development may guide the discovery of new targets for intervention. STUDY DESIGN/UNASSIGNED:Prospective cohort. SETTING & PARTICIPANTS/UNASSIGNED:703 African American Study of Kidney Disease and Hypertension (AASK) and 434 Boston Kidney Biopsy Cohort (BKBC) participants with baseline proteomics data. EXPOSURES/UNASSIGNED:Circulating proteins measured using SomaScan. OUTCOMES/UNASSIGNED:Kidney failure, defined as dialysis initiation or kidney transplantation. ANALYTICAL APPROACH/UNASSIGNED:Using adjusted Cox models, we studied associations of 6,284 circulating proteins with kidney failure risk separately in AASK and BKBC and meta-analyzed results. We then performed gene set enrichment analyses to identify underlying perturbations in biological pathways. In separate data sets with kidney-tissue level gene expression, we ascertained dominant regions of expression and correlated kidney tubular gene expression with fibrosis and estimated glomerular filtration rate (eGFR). RESULTS/UNASSIGNED:) participants developed kidney failure, respectively. We identified 143 proteins that were associated with incident kidney failure, of which only 1 (Testican-2) had a lower risk. Notable proteins included those related to vascular permeability (endothelial cell-selective adhesion molecule), glomerulosclerosis (ephrin-A1), glomerular development (ephrin-B2), intracellular sorting/transport (vesicular integral-membrane protein VIP36), podocyte effacement (pigment epithelium-derived factor), complement activation (complement decay-accelerating factor), and fibrosis (ephrin-A1, ephrin-B2, and pigment epithelium-derived factor). Gene set enrichment analyses detected overrepresented pathways that could be related to CKD progression, such as ephrin signaling, cell-cell junctions, intracellular transport, immune response, cell proliferation, and apoptosis. At the kidney level, glomerular expression predominated for genes corresponding to circulating proteins of interest, and several gene expression levels were correlated with eGFR and/or fibrosis. LIMITATIONS/UNASSIGNED:Possible residual confounding. CONCLUSIONS/UNASSIGNED:Multimodal data identified proteins and pathways associated with the development of kidney failure.